RABIES CASE PRESENTATIONMichelle Aguirre, PharmD

Medical Center Hospital

September 8th, 2017

PART I: CASE INTRODUCTION AND DISEASE OVERVIEW

Michelle Aguirre, PharmD

Medical Center Hospital

September 8th, 2017

CASE INTRODUCTION

Chief complaint

Unobtainable at the moment

History of present illness

JC is a 49-year-old male who was walking down the street and was drinking one liter of vodka roaming exhibiting signs of confusion. He was called by his neighbor to go back to his house, as it was hot in the day. The patient refused to go back to this home and had recurrent falls on his head and sustained multiple injuries on his limbs and left knee. Along his journey, a dog came and bit him on his left knee and then ran away. Afterwards, one of the neighbors called the ambulance and the patient was transferred to the ER for further care.

CASE INTRODUCTION

PMH Hypertension

Bipolar disorder

Chronic active alcoholism

Family history Unknown

Social history Drinks about one liter of vodka

every day for the last 20 years and has multiple admissions for alcohol withdrawal symptoms

Allergies Sulfa (reaction unknown)

Home Medications Seroquel 400 mg PO daily

Lithium 300 mg PO TID

Lisinopril 20 mg PO daily

CASE INTRODUCTION

Review of systems:

General appearance: Patient was awake and alert and in severe acute distress

Head: Normocephalic. No raccoon’s eyes or battle signs

Neck: Mild tenderness in the upper cervical spine/posterior scalp

Eyes: PERRLA, extraocular muscles intact

Respiratory: Lungs clear to auscultation bilaterally, no respiratory distress

Cardiovascular: Regular rate and rhythm, no murmurs, rubs, or gallops

Abdomen: Soft, nontender, nondistended

Neuro: GCS 15, awake alert, and oriented x4

Skin: Multiple bruises noted from patient’s posterior shoulder to his right flank; There is a large bruise over the patient’s left knee with good range of motion. Also, presence of dog bite with minor skin abrasions

Extremities: Left knee bruise, normal range of motion

CASE INTRODUCTION

Vital Signs

HR: 77 RR: 13 BP: 58/25 Temp: 101F Weight: 91kg Height: 6’6’’

Labs

Na 129 L Glucose 76 WBC 14.8 H

K 4.0 Mg Hgb 9.2

Cl 75 L Albumin 3.6 Plts 124 L

CO2 16 L AST 42 H Lact. Acid 3.1 H

BUN 112 H ALT 38 PT 18.0 H

SCr 20.6 H Bili 0.9 INR 1.53 H

CASE INTRODUCTION

JC is admitted to the ICU where the admitting physician decides to start this patient on a rabies vaccine schedule

The whole ICU team is now on the case and will follow the patient clinically and make adjustments as necessary

RABIES: BACKGROUND

Rabies is a zoonotic disease caused by RNA viruses in the family Rhabdoviridae, genus Lyssavirus

Virus is transmitted in the saliva of rabid mammals via a bite

After entry to the central nervous system, these viruses cause an acute progressive encephalomyelitis

The incubation period usually ranges from 1 to 3 months after exposure, but can range from days to years

The vast majority of rabies cases reported to the Centers for Disease Control and Prevention (CDC) each year occur in wild animals like raccoons, skunks, bats, and foxes

EPIDEMIOLOGY

Over the last 100 years, rabies in the United States has changed dramatically

More than 90% of all animal cases reported annually to CDC now occur in wildlife (before 1960, the majority were domestic animals)

The principal rabies hosts today are wild carnivores and bats

The number of rabies-related human deaths in the United states has declined from more than 100 annually at the turn of the century to one or two per year in the 1990’s

Prompt wound care and the administration of rabies immune globulin (RIG) and vaccine are highly effective in preventing human rabies following exposure

TRANSMISSION

The route of infection is usually, but not necessarily, by a bite

In many cases the affected animal is exceptionally aggressive, may attack without provocation, and exhibits otherwise uncharacteristic behavior

Transmission may also occur via an aerosol through mucous membranes (transmission in this form may have happened in people exploring caves populated by rabid bats)

Transmission between humans is extremely rare, although it can happen through transplant surgery, or, eve, more rarely through bites or kisses

Various routes of transmission have been documented and include contamination of mucous membranes (i.e., eyes, nose mouth), aerosol transmission, and corneal transplantations

PATHOPHYSIOLOGY: OVERVIEW

Infection by bite

• The virus directly or indirectly enters the peripheral nervous system

• It then travels along the nerves towards the central nervous system

Virus reaches brain

• Rapid encephalitis develops and symptoms appear

• The spinal cord may inflame producing myelitis

Perivascular infiltration

• Lymphocytes, polymorphonuclear leukocytes, and plasma cells may leak throughout the entire CNS

• Virus enters salivary glands and other organs of victim

Am J Vet Res. 1966 Jan;27(116):24-32

SIGNS AND SYMPTOMS

When a person contracts rabies, they do not show symptoms immediately

The disease takes a period of time to manifest in the body which is known as its period of incubation

Once symptoms arise, the patients condition deteriorates rapidly

FIVE STAGES OF RABIES

Incubation period: 5 days to > 2 years

U.S. median ~ 35 days

Pro-dome State: 0-10 days

Early flu-like symptoms

Acute neurologic period: 2-7 days

Neurologic symptoms begin

Coma: 5-14 days

Requires mechanical ventilation

Death

SIGNS AND SYMPTOMS

*Death usually occurs within day of the onset of late symptoms

Early Symptoms Late Symptoms

• Fever

• Headache

• Generalized weakness

• Generalized discomfort

• Insomnia

• Anxiety

• Confusion

• Slight or partial paralysis

• Excitation

• Hallucinations

• Agitation

• Hypersalivation

• Difficulty swallowing

• Hydrophobia

DIAGNOSIS

In animals, rabies is diagnosed using the direct fluorescent antibody (DFA) test, which looks for the presence of rabies virus antigens in brain tissue

Several tests are required in humans to diagnose rabies ante-mortem (before death); no single test is sufficient

Saliva can be tested by virus isolation or reverse transcription followed by polymerase chain reaction (RT-PCR)

Serum and spinal fluid are tested for antibodies to rabies virus

Skin biopsy specimens are examined for rabies antigen in the cutaneous nerves at the base of hair follicles

PART II: DRUG THERAPY DISCUSSIONSchizophrenia Final

Presentation

Michelle Aguirre, PharmD

Candidate 2017

EARLY MANAGEMENT

Wash any wounds immediately

One of the most effective ways to decrease the chance for infection is to wash the wound thoroughly with soap and water

Refer to a doctor

For attention for any trauma due to the animal attack before considering the need for rabies vaccination

The doctor, possibly in consultation with state or local health department, will decide on the need of rabies vaccination

Decisions to start vaccination, known as post-exposure prophylaxis (PEP) are up to the discretion of the physician, but two organizations have developed recommendations:

Advisory Committee on Immunization Practices (ACIP) schedule for rabies vaccine (2010)

World Health Organization (WHO) pre- and post-exposure prophylaxis 2010

EARLY MANAGEMENT

Post-exposure prophylaxis (PEP)

CDC recommends following ACIP 2010 vaccination schedule

Consists of one dose of immune globulin and four doses of rabies vaccine over a 14-day period

Rabies immune globulin and the first dose of rabies vaccine should be given by a health care provider as soon as possible after exposure

Additional doses or rabies vaccine should be given on days 3, 7, and 14 after the first vaccination

Current vaccines are relatively painless and are given in the arm, like a flu vaccine

Rabies immunoglobulin is referred to as “passive immunization” while rabies vaccine is referred to as “active immunization”

*Recommendations for PEP schedules are based on vaccination status: not previously vaccinated vs. previously vaccinated*

POST-EXPOSURE PROPHYLAXIS

Goal: To neutralize the virus at the site of infection before it can enter the human nervous system generally ensures survival

Rabies Immune Globulin

The administration of RIG provides immediate virus-neutralizing antibodies until protective antibodies are generated in response to vaccine

HRIG has a half-life of approximately three weeks

Two preparations of HRIG are licensed and available in the U.S.

Rabies Vaccines

Rabies vaccine induces the production for protective virus-neutralizing antibodies within approximately 7 to 10 days that persist for several years

Two licensed vaccines are currently available in the U.S.

DYNAMICS OF RABIES AND PEP

Figure 1. Schematic of dynamics of rabies virus pathogenesis in the presence and absence of PEP-mediated immune responses

NOT PREVIOUSLY VACCINATED

Intervention Regimen

Wound cleansing All PEP should begin with immediate thorough

cleansing of all wounds with soap and water. If

available, a virucidal agent (e.g., povidine-iodine

solution) should be used to irrigate the wounds

Human rabies

immune globulin

(HRIG)

Administer 20 IU/kg body weight on day 0. If

anatomically feasible, the full dose should be

infiltrated around and into the wound(s), and any

remaining volume should be administered

intramuscularly at an anatomical site distant from the

vaccine administration

Vaccine Human diploid cell vaccine (HDCV) or purified chick

embryo cell vaccine (PCECV) 1.0 mL, IM (deltoid

area), 1 each on days 0, 3, 7 and 14

PREVIOUSLY VACCINATED

Intervention Regimen

Wound cleansing All PEP should begin with immediate thorough

cleansing of all wounds with soap and water. If

available, a virucidal agent (e.g., povidine-iodine

solution) should be used to irrigate the wounds

Human rabies

immune globulin

(HRIG)

HRIG should not be administered

Vaccine Human diploid cell vaccine (HDCV) or purified chick

embryo cell vaccine (PCECV) 1.0 mL, IM (deltoid

area), 1 each on days 0 and 3

POST-EXPOSURE PROPHYLAXIS FOR UNVACCINATED PERSONS

1. The combination of RIG and vaccine is recommended for both bite and non-bite exposures, regardless of the time interval between exposure and initiation of PEP

2. If PEP has been initiated and appropriate laboratory diagnostic testing (i.e., the direct fluorescent antibody test) indicates that the animal that caused the exposure was not rabid, PEP may be discontinued

3. If HRIG was not administered when vaccination was begun on day 0, it can be administered up to and including day 7 of the PEP series

4. Even when PEP is administered imperfectly or not according to the schedule, it might generally be effective

OTHER KEY POINTS

HRIG is not administered in the same syringe or at the same anatomic site as the first vaccine dose

The gluteal area should not be used because administration of vaccine in this area may result in diminished immunologic response

Children should receive the same vaccine dose (i.e., vaccine volume) as recommended for adults

SEROLOGIC TESTING

All healthy persons tested in accordance with ACIP guidelines after completion of at least a 4-dose regimen of rabies PEP should demonstrate an adequate antibody response against rabies virus

No routine testing of healthy patients completing PEP is necessary to document seroconversion

When titers are obtained, serum specimens collected 1-2 weeks after prophylaxis should completely neutralize challenge virus

The titers will decline gradually since the last vaccination

ADVERSE REACTIONS AND PRECAUTIONS

Adverse effects with modern human rabies vaccination are uncommon

Pregnancy and infancy are not contraindications

Immunosuppression

All rabies vaccines licensed in the United States are inactivated cell-culture vaccines that can be administered safely to persons with altered immunocompetence

Use of corticosteroids, other immunosuppressive agents, antimalarials, and immunosuppressive illnesses might reduce immune responses to rabies vaccines and should receive a 5-dose vaccine regimen

PRICING AND AVAILABILITY

Rabies Immune Globulin

Injection (HyperRAB S/D Intramuscular) 150 units/mL (2mL): $852.14

Injection (Imogam Rabies-HT Intramuscular) 150 units/mL (2mL): $867.05

Rabies Virus Vaccine

Injection (Imovax Rabies Intramuscular) 2.5 units/mL (1): $386.76

Location at Medical Center Hospital

Immunoglobulin is stored in Gloria’s office in the first refrigerator

Vaccines are dispensed from the central pharmacy

WHO VACCINE RECOMMENDATIONS

Definition of categories of exposure and use of rabies biologicals from the World Health Organization (2010)

Immune globulin +

vaccine

Transdermal bites or scratches, licks on broken skin, contamination of mucous

membrane with saliva, or contact with bats

Vaccine only

Minor scratches or abrasions without bleeding or and nibbling of uncovered

skin

No prophylaxis

Touching, feeding of animals, or licks on intact skin

INFECTIOUS DISEASES SOCIETY OF AMERICA

Therapy Recommendation

Post-exposure

prophylaxis

• May be indicated; consultation with local health officials

is recommended to determine if vaccination should be

initiated

Skin and Soft Tissue Infection Guidelines (2014)

Specific recommendations are made for dog bites, including indications for antimicrobials

IDSA briefly mention PEP in their guidelines

PART III: CLINICAL COURSE Michelle Aguirre, PharmD

Candidate 2017

CLINICAL COURSE

Day 1: JC received the following regimen on day 0:

No documentation of wound care was found

Dog that bit patient was presumably killed by neighbor who owned dog

CLINICAL COURSE

Was this treatment appropriate?

Correct treatment

The recommendation is to administer:

Immune globulin 20 IU/kg x 91 kg = ~18,000 units

Chick embryo cell vaccine 2.5 mL/mL x 2.5 mg = 1 mL

Both should be given intramuscularly on day 0!

However, we do not know if he received proper wound care…

CLINICAL COURSE

Days that followed:

Is this regimen appropriate?

Day 0RIG and vaccine 1

1 mL

Day 4Vaccine 2

1 mL

Day 7Vaccine 3

1 mL

Day 12Patient

discharged

Day 14Scheduled vaccine

never given

PATIENT COURSE CONCLUSION

JC received the correct doses for RIG and vaccines

ACIP recommends immune globulin + vaccines (CDC preferred); WHO classification is difficult to determinebut likely recommends vaccine only for this patient

Wound care was never documented in the patient chart

± Although the treatment plan did not follow the vaccine schedule days exactly and the patient did not receive the last vaccine, he is expected to have some general immunity

QUESTIONS?

REFERENCES

1. CDC. Rabies. Centers for Disease Control and Prevention [cited September 1, 2017]. Available from [https://www.cdc.gov/rabies/index.html].

2. CDC. Rabies prevention – Unites States, 2010: recommendations of the Immunization Practices Advisory Committee (ACIP). Y40(No. RRR-3)

3. Dietzschold B, Schnell M, Koprowski H. Pathogenesis of rabies. Curr Top Microbiol Immunol. 2005;292:45-56.

4. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis. 2014;59(2):147-59.